Advanced mass spectrometry-based characterisation of plasma in the context of oesophageal cancer, obesity, and metal-protein interactions

Abstract

This thesis sought to investigate the systemic molecular alterations in the plasma proteome, metallome and metabolome across metabolic and oncological disease, offering a comprehensive characterisation of circulating biomolecules that drive physiological adaptation and pathological responses. The primary objective was to decipher how changes in plasma composition reflect underlying molecular remodelling during disease progression and recovery using a range of high-throughput omics approaches.

Proteomic, metabolomic, and metalloproteomic analyses were conducted to explore systemic molecular changes in oesophageal adenocarcinoma (OAC) and metabolic diseases. SWATH-MS proteomics of OAC plasma identified distinct molecular signatures linked to treatment response: responders to chemotherapy showed increased immune-related proteins, while those responding to chemoradiotherapy exhibited activation of haemostatic and regenerative pathways. Poor responders in both groups displayed proteolytic suppression and immune-metabolic imbalance. Metabolomic profiling via LC-MS/MS pinpointed propionyl-carnitine as a potential marker of favourable chemotherapy response. Conversely, multiple metabolites involved in amino acid, nucleotide, choline, and arginine metabolism were associated with poor chemoradiotherapy outcomes, indicating metabolic pathway reprogramming associated with resistance. Longitudinal SWATH-MS analysis of plasma from patients undergoing Roux-en-Y gastric bypass revealed systemic proteomic reorganisation, including increased SHBG, ITIH3, and ApoD, along with decreased coagulation proteins (A2M, KLKB1, F10–F12), suggesting lowered thrombotic risk and better vascular health. Metalloproteomic studies showed coordination between plasma proteins and trace elements, implying that kininogen may compensate for Zn²⁺ binding when albumin affinity shifts. Notably, ceruloplasmin and transferrin strongly correlated with copper and iron levels, respectively.

Collectively, this thesis highlights the potential of plasma proteins and their ability to dynamically respond to diverse pathological states and metabolic conditions and the ability to quantify these changes using high-throughput MS techniques. Thus, this work highlights the cutting-edge MS-driven omics strategies in elucidating disease mechanisms, providing a foundation for biomarker discovery, mechanistic validation and the advancement of translational and systems medicine.

Date of Award	3 Jul 2026
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Alan J. Stewart (Supervisor), Sally Shirran (Supervisor) & Marco Ferreira Fernandes (Supervisor)